Process for preparing enamine phosphorus compounds

ABSTRACT

REAGENTS FOR ALDEHYDE SYNTHESIS, PARTICULARLY FOR FORMYL-OLEFINATION, OF THE GENERAL FORMULA:   R1-O-P(=O)(-R2)-C(-R4)=CH-NH-R3   WHEREIN R1 REPRESENTS A LOWER ALKYL GROUP, R2 REPRESENTS R10 OR ANALKYL, ARALKYL OR ARYL GROUP, R3 REPRESENTS AN ACYCLIC OR CYCLIC ALKYL OR ARYL GROUP, AND R4 REPRESENTS A HYDROGEN ATOM, AN ALKYL, ARALKYL OR ALKOXYCARBONYL GROUP OR A HALOGEN ATOM, WHICH REACT WITH CARBONYL COMPOUNDS &gt;C=O TO YIELD A,B-UNSATURATED ALDEHYDES OF TGE GENERAL FORMULA:   -C(=C(-R4)-CHO)-   WHEREIN R4 HAS THE SAME MEANING AS DESCRIBED ABOVE.

United States Patent 3,816,570 PROCESS FOR PREPARING ENAMINE PHOSPHORUS COMPOUNDS Wataru Nagata, Nishinomiya, and Yoshio Hayase, Sakai, Japan, assignors to Shionogi & (30., Ltd., Osaka, Japan No Drawing. Original application Feb. 27, 1969, Ser. No. 830,106, now Patent No. 3,673,284. Divided and this application Apr. 10, 1972, Ser. No. 242,781 Claims priority, application Japan, Mar. 7, 1968, 43/14,901; Mar. 19, 1968, 43/18,134, 43/18,135; Mar. 30, 1968, 43/20,805

Int. Cl. C07f 9/38 U.S. Cl. 260-968 2 Claims ABSTRACT OF THE DISCLOSURE Reagents for aldehyde synthesis, particularly for formyl-olefination, of the general formula:

wherein R represents a lower alkyl group, R represents R 0 or an alkyl, aralkyl or aryl group, R represents an acyclic or cyclic alkyl or aryl group, and R represents a hydrogen atom, an alkyl, aralkyl or alkoxycarbonyl group or a halogen atom, which react with carbonyl compounds C=O to yield 0:, 3-11I1Sflilllfli6d aldehydes of the general formula:

wherein R has the same meaning as described above.

This is a division of application Serial No. 830,106, filed Feb. 27, 1969, now U.S. Pat. 3,673,284.

The present invention relates to novel reagents for aldehyde synthesis, to processes for the preparation thereof and to uses thereof.

More particularly, the present invention relates to novel reagents for formyl-olefination represented by the general formula:

wherein R is a lower alkyl group, R is a member selected from the group consisting of R 0, a lower alkyl group, an aralkyl group of 7-8 carbon atoms and an aryl group of 6-7 carbon atoms, R is a member selected from the group consisting of an acyclic or cyclic alkyl group of 1-6 carbon atoms and an aryl group of 6-7 carbon atoms, and R is a member selected from the group consisting of a hydrogen atom, a lower alkyl group, an aralkyl group of 7-8 carbon atoms, a lower alkoxycarbonyl group, and a halogen atom.

The methods for preparing c p-unsaturated aldehydes, so-called forrnyl-olefination, consisting of adding two carbon atoms to carbonyl functions as illustrated by the accompanying equation, have widely been utilized as useful synthetic method in chemical or pharmaceutical industries, particularly in preparations of pharmaceutically useful compounds such as various steroids, vitamin A, vitamin D, carotenoids and other natural products or medicaments or intermediates thereof.

3,816,570: Patented June 11, 1974 ice Representative of the methods is indirect one including modifications thereof, consisting of adding an acetylenic anion to a carbonyl compound followed by rearrangement to desired a,,B-unsaturated aldehyde, for example,

[G. Saucy et al., Helv. Chim. Acta, 42, 1952 (1959).] However, these methods are disadvantageous in requirement of multi-step reactions or in low yield or in limitation of application.

Alternative most striking methods are so-called aldolcondensation consisting of condensing an active methylene group adjacent to an aldehyde group with another carbonyl group.

In general, the various methods for reacting the compounds involving an active methylene group adjacent to the electron withdrawing group (e.g. nitro group, carbonyl group, sulfonyl group, a carboxylic acid ester, cyano group etc.) with other carbonyl compounds have been known as well as that of the active methylene group adjacent to aldehyde (aldol-condensation). However, these reactions are accompanied by side-reactions undesirable for the objective reaction in many cases, such as self-condensation or polymerization, since the reactions are usually carried out in the presence of a basic catalyst. In order to remove these side-reactions, various methods, for example, Mannich reaction, Darzen condensation, Reformatsky reaction, have been reported. However, the satisfactory process for formyl-olefination has been unknown.

On the contrary, the process for preparing olefins consisting of reacting a carbonyl compound with a phosphonium ylide compound, so-called Wittig reaction, is very useful reaction for introducing the terminal methylene to carbonyl group or further increasing the hydrocarbon chain a well as Grignard reaction. Attempts to apply this reaction to the aldol-condensation type reaction, for example, the reactions by the ylide compounds involving the electron withdrawing group adjacent to the methylene group in the opposite side against the phosphonium group, as indicated by the formulae II-V, have been known. However, the nucleophilicity of the reagents to the carbonyl compounds decreases due to the electron-delocalization, for

example, as indicated in the following equation. Accordingly, the reactivity of the reagents is remarkably low in comparison with the Wittig reagents involving no electron withdrawing group in the adjacent position. For example, the abovedescribed compound V reacts with benzaldehyde to yield cinnamic aldehyde, while not reacting with ketones. Furthermore, the compound V does not react with an aldehyde located at the sterically hindered position (e.g. an aldehyde located at the tertiary position) [Trippett and Walker, J. Chem. Soc., 1266 (1961)].

Wadsworth and his co-workers developed the reaction method using phosphonate carbanion as a modification of the Wittig reaction [J Am. Chem. Soc., 83, 1733 (1961)]. This reaction may be characterized by utilizing the phosphonate carbanion more reactive than the Wittig reagent in order to increase the reactivity of the active methylene compounds involving the electron withdrawing group in the adjacent position. For example, the reactivity of the reagents represented by the following formulae VI--IX, involving the electron withdrawing group in the adjacent position, could considerably be increased sequence as follows:

roon G I ex -oc,rn 2 a)2PCH-CH\ OCzHt Therefore, in spite of these various attempts, the sufiicient process for formyl-olefination has not yet been developed.

The present inventors had studied various methods in order to remove these disadvantages and it has been dis- 'covered that the enamine-type phosphonate compounds represented by the above-described general formula I have been excellently elfective as reactive agents for preparing u,}3-unsaturated aldehyde by condensing aldehydes involving the active methylene group at the a-position with other carbonyl compounds. The reactive agents of the present invention may be applied to all sorts of carbonyl compounds including aldehydes and ketones and efiectively show remarkable reactivity even to the hindered carbonyl compounds such as aldehydes located at the tertiary position. Furthermore, the method of the present invention is much more effective than the above-mentioned other methods in stability of the reagents in reaction medium, in easiness of the reaction procedure, in improvement of the yield or in stereospecificity.

Each substituent of the reagents represented by the above-mentioned general formula I is more precisely indicated as follows: R represents a lower alkyl group such as methyl, ethyl, n-propyl, n-butyl or the like, R has the same meaning as R 0 or is a member selected from the group consisting of a lower alkyl group such as methyl, ethyl, n-propyl, n-butyl or the like, an aralkyl group of 7-8 carbon atoms such as benzyl, phenylethyl, tolubenzyl or the like, and an aryl group of 6-7 carbon atoms such as phenyl, tolyl or the like, R is a member selected from the group consisting of an acyclic or cyclic alkyl group of 1-6 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, nbutyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, s-pentyl, t-pentyl, n-hexyl, cyclopentyl cyclohexyl or the like, and an aryl group of 6-7 carbon atoms, and R is a member selected from the group consisting of a hydrogen atom, a lower alkyl group such as methyl, ethyl, n-propyl i-propyl, n-butyl, n-pentyl, n-hexyl or the like, an aralkyl group of 7-8 carbon atoms such as benzyl, phenylethyl, tolubenzyl or the like, a lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl or the like, and a halogen atom such as chlorine, bromine or iodine atom.

Dimethylphosphonoacetaldehyde methylamine enamine,

Dimethylphosphonoacetaldehyde i-propylamine enamine,

Dimethylphosphonoacctaldehyde t-butylamine enamine,

Dimethylphosphonoacetaldehyde cyclohexylamine enamine,

Diethylphosphonoacetaldehyde methylamine enamine,

Diethylphosphonoacetaldehyde i-propylamine enamine,

Diethylphosphonoacetaldehyde t-butylamine enamine,

Diethylphosphonoacetaldehyde cyclohexylamine enamine,

Diethylphosphonoacetaldehyde analine enamine,

Di-n-propylphosphonoacetaldehyde t-butylamine enamine,

Di-n propylphosphonoacetaldehyde cyclohexylamine enamine, Z-Dimethylphosphonopropionaldehyde t-butylamim enamine, Z-Dimethylphosphonopropionaldehyde cyclohexylamine enamine,

2-Diethylphosphonopropionaldehyde t-butylamine enamine,

2-Diethylphosphonopropionaldehyde cyclohexylamine enamine,

2-Diethylphosphono-n-butyraldehyde t-butylamine enamine,

2-Diethylphosphono-n-butyraldehyde cyclohexylamine enamine,

2-Diethylphosphono-n-valeraldehyde t-butylamine enamine,

2-Diethylphosphono-n-valeraldehyde cyclohexylamine enamine,

2-Diethylphosphono-3-phenylpropionaldehyde cyclohexylamine enamine,

2-Diethylphosphono-3- (N-cyclohexyl) aminoacrylic acid ethyl ester,

Z Diethylphosphono-2-bromoacetaldehyde cyclohexylamine enamine,

2-Diethylphosphono-2-chloroacetaldehyde t-butylamine enamine,

Ethyl-2-cyclohexylaminovinyl phenylphosphinate,

Ethyl-1-methy1-2-cyclohexylaminovinyl phenylphosphinate,

Ethyl-l-ethyl-2-cyclohexylaminovinyl phenylphosphinate,

Ethyl-( l-benzyl-2-cyclohexylamino)vinyl phenylphosphinate,

Ethyl-2-t-butylaminovinyl phenylphosphinate,

Ethyl-( 1-methyl-2-t-butylamino)vinyl phenylphosphinate,

Ethyl-( l-benzyl-Z-t-butylamino)vinyl phenylphosphinate,

EthyI-Z-t-butylaminovinyl ethylphosphinate, and

Ethyl-Z-cyclohexylamino ethylphosphinate.

The reagents (I) of the present invention may be prepared from the compounds of the general formula X as illustrated by the following reaction sequence,

Ib (R =R but a hydrogen atom in I) wherein R R R and R each has the same meanings as described above.

The compounds (X) in the above-described reaction sequence may be prepared according to the known method as follows:

(R O OCzHs P BrCHrCH 3 O CzHI XI XII R 0 0 OCrHa I"-CH2CH X XIII wherein R and R each has the same meanings as described above, the acetal derivative of ot-bromoacetaldehyde of the general formula XII is subjected to reaction with the phosphite derivative of the general formula XI and then the acetal protecting group of the resulting phosphinate derivative (XIII) is removed to the compound (X).

The reagents (Ia: R=H in I) can be prepared by reacting the compounds (X) with the primary amines represented by the general formula R NH in a suitable solvent (e.g. methanol, ethanol, n-propanol, t-butanol, benzene, toluene, tetrahydrofuran etc.) or without any solvent at a temperature ranging from 0 C. to 120 C. The reaction may be carried out according to the process for preparing so-called SchifI-base or the process for enamine formation.

The reagents (Ib: R '=R but a hydrogen atom in I) can be prepared by further reacting the compounds (Ia) with the compounds, capable of releasing the radical R represented by the general formula R 'X in the presence of a catalyst.

The compounds of the general formula R X are alkyl halogenides consisting of an alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, n-pentyl, n-hexyl or the like and a halogen atom such as chlorine, bromine or iodine atom (e.g. methyl iodide, ethyl bromide, n-butyl iodide, n-hexyl bromide etc.), aralkyl halogenides consisting of an aralkyl group such as benzyl, phenylethyl, tolubenzyl or the like and a halogen atom (e.g. benzyl chloride, phenylethyl bromide, tolubenzyl iodide etc.), lower alkoxycarbonyl halides such as methyl chloroformate, ethyl chloroformate or the like, and halogenating agents. The halogenating agents in this process mean the reagents producing the positively charged halogen atom in the reaction medium, for example, chlorine (C1 bromine (Br iodine (I cyanogen bromide, cyanogen iodide, N-bromoacetamide (NBA), N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), N-chloro-p-toluenesulfonamide (chloramine N-chlorobenzenesulfonamide (chlormine B), t-butyl hypochlorite, pyridinium bromide perbromide and the like.

The reaction of the compounds (Ia) with the compounds R X is usually carried out in a suitable inert solvent in the presence of a catalyst under cooling or at room temperature (about 30-40 C.), if necessary, under heating (such as refluxing temperature). The catalysts used in the reaction are, for example, lithium, sodium, lithium hydride, sodium hydride, sodium amide, potassium amide, Grignard reagents such as ethylmagnesium bromide, methylmagnesium iodide, ethylmagnesium chloride and the like, and organo metal compounds such as butyl lithium, phenyl lithium and the like. The preferred solvents are ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, diglyme and the like, and hydrocarbon solvents such as benzene, toluene, xylene and the like.

The resulting reagents (I) of the present invention may be applied to preparation of nap-unsaturated aldehydes (XIV) increasing two carbon atoms from carbonyl 6 compounds C=O as illustrated by the following reaction sequence:

XIV

wherein R has the same meanings as described above.

The carbonyl compounds applicable to the reagents (I) in the present invention are those, involving aldehyde or ketone, of acyclic compounds, monocyclic or polycyclic compounds such as terpenes, steroids, carotenoids or the like, or mono or poly-condensed aromatic compounds (i.e. aldehydes located at the primary, secondary or tertiary position, aromatic aldehydes, acyclic ketones, cyclic ketones, aromatic ketones etc.).

The reaction of the reagents (I) with the carbonyl compounds O=O is usually carried out in an aprotic solvent in the presence of a basic catalyst. The usual reaction procedure may be indicated as follows: the reagent represented by the general formula (I) is dissolved in an aprotic solvent with a basic catalyst to form the anion represented by the following general formula:

wherein R R R and R each has the same meanings as described above, and then the starting carbonyl compound C= is added to this solution. However, the reaction is not always carried out according to such successive procedure. For example, the reaction may also be carried out by adding the basic catalyst into the previously prepared solution of the starting carbonyl compound and the reagent (I) in an aprotic solvent.

The basic catalysts used are metal alcoholate such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium t-butoxide, sodium tbutoxide and the like, sodium amide, potassium amide, lithium diethylamide, sodium hydride, lithium hydride, lithium triphenylmethide, methyl lithium, butyl lithium or Grignard reagents such as methyl-magnesium bromide, ethylmagnesium bromide and the like.

Aprotic solvents, i.e. the solvent releasing no proton, are, for example, ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and the like, hydrocarbon solvents such as benzene, toluene, xylene and the like, N, N-dimethylformamide and the like.

The reaction temperature may be set according to the reactivity of the carbonyl compounds applied and the reaction may be carried out at room temperature or under cooling or sometimes under heating. Moreover, the reaction is preferably carried out under an inert gas such as nitrogen or argon, because of the reaction in the presence of a strongly basic catalyst. Furthermore, the reaction is preferably carried out under stirring in order to etfectively proceed the reaction.

The products obtained in the above-described process are the Schitf-bases involving the partial structure represented by the general formula XV,

wherein R and R each has the same meanings as described above. Accordingly, the products must be hydrolyzed as usual manner with an acid or base to regenerate the aldehyde group. In general, the products without the isolation as the intermediates are preferably subjected to the acid hydrolysis consisting of the two phase system. The preferred acid medium is a diluted solution of oxalic acid or a buffer solution such as acetic acid-sodium acetate-water, tartaric acid-sodium tartarate-water or the like.

Thus resulting il-unsaturated aldehydes (XIV) may be isolated and purified according to the usual isolation and purification procedure used in the general synthetic chemistry, for example, extraction, distillation, recrystallization, column chromatography, thin layer chromatography, gas chromatography, or the methods by so-called carbonyl reagents (e.g. Girard reagents, hydrazone, semicarbazone, oxime etc.).

The invention will be better explained by the following examples which are not intended as a limitation thereof.

EXAMPLE 1 Diethylphosphonoacetaldehyde cyclohexylamine enamine To a solution of 30.2 g. of diethylphosphonoacetaldehyde in 90 ml. of anhydrous methanol, there is added 19.2 ml. of purified cyclohexylamine in nitrogen atmosphere under ice-cooling and stirring. The reaction mixture is kept at room temperature for minutes under stirring and then the solvent is distilled ofi under reduced pressure. The residue is dissolved in 150 ml. of anhydrous ether, dried over anhydrous potassium carbonate, and then evaporated under reduced pressure. The resulting residue is purified by highly vacuum distillation in the presence of 300 mg. of potassium carbonate to afford 33.06 g. of diethylphosphonoacetaldehyde cyclohexylamine enamine (75.4% yield) having b.p. 151l52 C./ 0.04 mm. Hg. The purity of this substance is confirmed by gas chromotography.

UV: 155,35 241 m (6 16,300 IR: .33 3255, 1633 (shoulder), 1620, 1211, 1058, 1035, 955 cum- NMR: 6 (CCl 1.25 (triplet), 3.25 (multiplet), 3.85 (multiplet), 6.7 (multiplet) p.p.m. Anal.-Calcd. for C H O NP: C, 55.15; H, 9.26; N, 5.36; P, 11.86. Found: C, 54.54; H, 9.55; N, 5.43; P, 12.08.

EXAMPLE 2 According to the same procedure as Example 1, dimethylphosphonoacetaldehyde t-butylamine enamine, diethylphosphonoacetaldehyde t-butylamine enamine, ethyl- 2-cyclohexylaminovinyl phenylphosphinate, and ethyl-Z-tbutylarninovinyl ethylphosphinate are prepared, respectively.

EXAMPLE 3 2-diethylphosphonopropionaldehyde cyclohexylamine enamine To a solution of 10.0 g. of diethylphosphonoacetaldehyde cyclohexylamine enamine in 30 ml. of anhydrous tetrahydrofuran, there is added dropwise 22.0 ml. of ethylmagnesium bromide-tetrahydrofuran solution (2.31 mM./ml.) within a period of 20 minutes under ice-cooling and stirring. After stirring for 40 minutes at room temperature, a solution of 8.10 g. of methyl iodide in 10 ml. of anhydrous tetrahydrofuran is added dropwise and then the reaction mixture is refluxed for 1.5 hours. After cooling, the reaction mixture is poured into ice-water, extracted with dichloromethaue-ether (1:3), washed with saturated sodium chloride aqueous solution and then evaporated under reduced pressure to yield 7.09 g. of residue, which on crystallization from ether-pentane affords 7.00 g. of 2 diethylphosphonopropionaldehyde cyclohexylamine enamine (66.6% yield) having m.p. 61-64 C./ 73 C. (double melting point).

UV: x532 246 mu (e 24,200 IR: .ggg' 3265, 1642, 1221, 1057, 1031, 951 5111- Anal.Calcd. for C H O NP: C, 56.71; H, 9.52; N, 5.09; P, 11.25. Found: C, 56.52; H, 9.59; N, 5.25; P, 11.20.

8 EXAMPLE 4 2-diethylphosphono-3-phenylpropionaldehyde cyclohexylarnine enamine To a solution of 2.85 g. of diethylphosphonoacetaldehyde cyclohexylamine enamine in 10.0 ml. of anhydrous tetrahydrofuran, there is added dropwise 6.86 ml. of 2.39 N ethylmagnesium bromide-tetrahydrofuran solution within a period of 10 minutes under ice-cooling and stirring. After stirring for 1 hour under ice-cooling, a solution of 1.38 g. of benzyl chloride in 4.0 ml. of anhydrous tetrahydrofuran is added dropwise within a period of 5 minutes and. then the reaction mixture is refluxed for 22 hours. After cooling, the reaction mixture is poured into icewater, extracted with ether, Washed with water, dried over anhydrous sodium sulfate and then evaporated to dryness to yield 3.09 g. of residue, which on crystallization from ether-pentane affords 2.72 g. of 2-diethylphosphono-3- phenylpropionaldehyde cyclohexylamine enamine (71.2% yield) having m.p. 7982 C.

UV: x5 3 246.5 mp. (e 15,960). IR: .ggg 3406, 1636 1603, 1235, 1057, 1031, 950 cmf Anal.-Calcd. for C H O NP: C, 64.93; H, 8.61; N, 3.99; P, 88.2. Found: C, 65.35; H, 8.92; N, 4.04; P, 9.16.

EXAMPLE 5 According to the same procedure as Examples 3 and 4, 2-diethylphosphonopropionaldehyde t-butylamine enamine, ethyl l methyl-2-cyclohexaminovinyl phenylphosphinate, and ethyl- 1-benzyl-2-cyclohexylamino vinyl phenylphosphinate are prepared, respectively.

EXAMPLE 6 2-diethylphosphono-3-(N-cyclohexyl) aminoacrylic acid ethyl ester To a solution of 4.00 g. of diethylphosphonoacetaldehyde cyclohexylamine enamine in 12.0 ml. of anhydrous tetrahydrofuran, there is added dropwise 9.6 ml. of 2.39 N ethylmagnesium bromide-tetrahydrofuran solution within a period of 10 minutes under ice-cooling and stirring. After stirring for 1 hour at room temperature, a solution of 1.65 g. of ethyl chloroformate in 10 ml. of anhydrous tetrahydrofuran is added dropwise within a period of 5 minutes under ice-cooling and then the reaction mixture is stirred for additional 3 hours at the same temperature. The reaction mixture is poured into ice-water, extracted with ether, washed with water, dried over anhydrous sodium sulfate and then evaporated to dryness to yield 4.37 g. of residue, which on purification by highly vacuum distillation affords 4.12 g. of 2-diethylphosphono-3-(N- cyclohexyDaminoacrylic acid ethyl ester (80.4% yield) having b.p. -147 C./0.002-0.003 mm. Hg.

UV: xgggg 240, 274 m (e 12,500, 9,130). IR: .2 3431, 3271, 1725, 1686, 1661, 1616 omf Anal.Calcd. for C H O NP: C, 54.04; H, 8.47; N, 4.20; P, 9.29. Found: C, 54.04; H, 8.63; N, 4.02; P, 9.64.

EXAMPLE 7 2-diethylphosphono-2-bromoacetaldehyde cyclohexylarnine enamine To a solution of 5.00 g. of diethylphosphonoacetaldehyde cyclohexyla mine enamine in 15.0 ml. of anhydrous tetrahydrofuran, there is added dropwise 11.3 ml. of 2.39 N ethylmagnesium bromide-tetrahydrofuran solution within a period of 10 minutes under ice-cooling and stir ring. After stirring for 30 minutes at room temperature, a solution of 2.02 g. of cyanogen bromide in 10.0 ml. of anhydrous tetrahydrofuran is added dropwise within a period of 5 minutes under ice-cooling and then the reaction mixture is stirred for 2.5 hours at room temperature. The reaction mixture is poured into ice-water, extracted with ether, washed with water, dried over anhydrous sodium sulfate and then evaporated to dryness to yield 5.96 g. of crude crystals, which on recrystallizafrom ether-pentane aiford 4.94 g. of Z-diethylphospho'no- 2-bromoacetaldehyde cyclohexylamine enamine (75.8% yield) having m.p. 7980 C.

UV: 15135 245 111,. (6 16,700). IR: 553, 1 1242, 1056, 1031, 902 cm."

Anal.Calcd. for C H O NPBr: C, 42.36; H, 6.81; N, 4.12; P, 9.11; Br, 23.49. Found: C, 42.26; H, 2.06; N, 4.24; P, 9.84; Br, 23.62.

EXAMPLE 8 5,8-frmylethylene-6B-vinyl-B-nor-androstan-3a-ol To a mixture of 386 mg. of 52.9% sodium hydride and 1.5 ml. of tetrahydrofuran, there is added a solution of 2.221 g. of diethylphosphonoacetaldehyde cyclohexylamine enamine in 14.5 ml. of anhydrous tetrahydrofuran under ice-cooling and stirring, and then stirring is continued for 15 minutes. A solution of 1.19 g. of p-formyl- 6f3-vinyl-B-nor-androstan-3a-ol benzoate in 7.0 ml. of anhydrous tetrahydrofuran is then added and the resulting solution is kept at room temperature for 3.5 hours under stirring. Further, 300 mg. of paraformaldehyde is added under ice-cooling and the reaction mixture is stirred for 30 minutes, then poured into ice-water, and extracted with ether-dichloromethane (4:1). The extract is washed with saturated sodium chloride aqueous solution and the solvent is evaporated to dryness to yield 2.686 g. of residue. To a solution of this residue in 25 ml. of benzene, there is added 1.7 g. of oxalic acid and 75 ml. of water. After the solution is kept overnight at room temperature under stirring, the benzene layer is separated and the aqueous layer is extracted with ether-dichloromethane (6:1). The extract combined with the benzene layer is washed with saturated sodium chloride aqueous solution and then the solvent is evaporated to dryness to yield 1.658 g. of residue. The residue is dissolved in 130 ml. of methanol and heated with 40 ml. of 2 N-potassium carbonate solution for 20 minutes under refluxing. The reaction mixture is concentrated under reduced pressure, poured into ice-water, and then extracted with etherdiehloromethane (4:1). The extract is evaporated under reduced pressure to yield 1.339 g. of residue, which is passed through a column of 30 g. of silica gel (containing 3% of water). Eluate with benzene-chloroform (1:1) is recrystallized from ether-pentane to afford 840 mg. of 5fi-formylethylene 6B vinyl B nor-androstan-3a-ol (87% yield) having m.p. 6 2-65 C.

EXAMPLE 9 3-formylmethylene-5a-androstan-170-01 benzoate To a mixture of 73 mg. of 52.9% sodium hydride and 1.0 ml. of tetrahydrofuran, there is added a solution of 398 mg. of diethylphosphonoacetaldehyde cyclohexylamine enamine in 2.0 ml. of anhydrous tetrahydrofuran under ice-cooling and stirring, and then the stirring is continued for 15 minutes. A solution of 500 mg. of 17 3-benzoyloxy-5a-androstan-3-one in 4.0 ml. of anhydrous tetrahydroturan is then added and the resulting solution is kept at room temperature for 3.5 hours under stirring. The reaction mixture is poured into ice-Water and the product is extracted with ether, washed with water and evaporated to dryness to yield 782 mg. of residue. To a solution of this residue in 30 ml. of benzene, there is added 800 mg. of oxalic acid and 90 ml. of water. After the solution is kept at room temperature for 17 hours under stirring, the benzene layer is separated and the aqueous layer is extracted with ether. The extract combined with the benzene layer is Washed with water and evaporated to dryness to yield 551 mg. of crystalline residue, which on recrystallization from ether affords 426 mg. of 3-formylmethylene-5a-androstan-17,8-01 benzoate (80% yield) having mp. 157-158 C.

UV: Age 235 m (6 21,700 IR: .ggg 2783, 1683, 1532, cmf NMR: 5 01301, 5.82 (doublet), 10.30 (doublet) p.p.m.

Anal.Calcd. for C H 'O C, 79.96; H, 8.63. Found: C, 79.49; H, 8.68.

EXAMPLE 10 3 fl-hydroxy- 17 (20) -5u-pregnen-21al To a mixture of 59.7 mg. of 52.9% sodium hydride and 1.0 ml. of tetrahydrofuran, there is added a solution of 342 mg. of diethylphosphonoacetaldehyde cyclohexylamine enamine in 2.0 ml. of anhydrous tetrahydrofuran under ice-cooling and stirring, and then stirring is con tinued for 15 minutes. A solution of 164 mg. of 3,8-tetrahydropyranyloxy-Sa-androstan-17-one in 1.5 ml. of anhydrous tetrahydrofuran is then added and the resulting solution is kept at room temperature for 10 hours under stirring. The reaction mixture is poured into ice-water and the product is extracted with ether, washed with water and evaporated to dryness to yield 343 mg. of residue. To a solution of this residue in 12 ml. of benzene, there is added 445 mg. of oxalic acid and 36 ml. of water. After the solution is kept at room temperature for 22 hours under stirring, the benzene layer is separated and the aqueous layer is extracted with ether. The extract combined with the benzene layer is washed with 2 N hydrochloric acid and then with water and evaporated to dryness to yield 208 mg. of residue. The residue is dissolved in 20 ml. of 70% acetic acid and heated at 6070 C. for 30 minutes. The reaction mixture is evaporated under reduced pressure, poured into ice-cooled saturated potassium carbonate aqueous solution and then extracted with ether. The extract is washed with water and evaporated to dryness to yield 132 mg. of crude crystals, which on recrystallization from dichloromethane-ether afford 99 mg. of 3fi-hydroxy-17(20)-5a-pregnen-21-al (71.2% yield) having m.p. 176-180 C.

UV: 5553 245 m (6 14,500 IR: 5338 2758, 1669, 1640, 1610 cm.- NMR: 6 (CD01 5.69 (multiplet), 9.78 (doublet) p.p.m.

Anal.Calcd. for C H O C, 79.70; H, 10.19. Found: C, 79.07; H, 10.12.

EXAMPLE 11 5 a-formylethylenepregnane-3,ZO-dione To a mixture of mg. 52.9% sodium hydride and 0.5 ml. of tetrahydrofuran, there is added a solution of 605 mg. of diethylphosphonoacetaldehyde cyclohexylamine enamine in 1.0 ml. of anhydrous tetrahydrofuran under ice-cooling and stirring, and then stirring is continued for 15 minutes. Then a solution of 100 mg. of 3,3:20,20-bisethylenedioxy-5a-formylpregnane in 2.0 ml. of anhydrous tetrahydrofuran is added and the resulting solution is refluxed for 9 hours. Thereafter, according to the same procedure as Example 3, the reaction product is treated with 840 mg. of oxalic acid and 30 ml. of water and then with 30 ml. of 70% acetic acid. Thus resulting product is crystallized from ether to afford 71 mg. of 50a formylethylenepregnane-3,20-dione (82.7% yield) having m.p. -144 C.

UV: 220.5 111,. (613,850). IR: liggf 2735, 1095, 1623 cmf NMR: 6 (CD01 6.13 (quartet, J=16 c.p.s.), 7.27 (doublet, J=16 c.p.s.), 9.52 (doublet) p.p.m.

Anal.Calcd. for C H O C, 77.80; H, 9.25. Found: C, 77.80; H, 9.25.

EXAMPLE 12 17 (20)-5apregnen-21-al To a mixture of 99 mg. of 52.9% sodium hydride and 1.4 ml. of tetrahydrofuran, there is added a solution of 568 mg. of diethylphosphonoacetaldehyde cyclohexylamine enamine in 2.2 ml. of anhydrous tetrahydrofuran under ice-cooling and stirring, and then stirring is continued for 15 minutes. Then, a solution of 200 mg. of a-androstan-17-one in 1.4 ml. of anhydrous tetrahydrofuran is added and the resulting solution is kept at room temperature for hours. The reaction mixture is treated in usual manner, and the product is dissolved in 35 ml. of benzene. The solution, to which is added 1.05 g. of oxalic acid and 105 ml. of water, is kept at room temperature for 13 hours under stirring. Thereafter, the product worked up as usual manner is crystallized from ether to aflFord 162 mg. of 17(20)-5a-pregnen- 21-al (74.0% yield) having mp. ISO-152 C.

UV: x1339 245 m... (6 16,500). 118.: .339 2758, 1670, 1640, 1610, cur- NMR: 6 (CD01 5.73 (multiplet), 9.87 (doublet) p.p.m.

AnaL-Calcd. for c H o; c, 83.94; H, 10.73. Found: 0, 83.69; H, 10.78.

EXAMPLE 13 Cinnamic aldehyde To a mixture of 653 mg. of 52.9% sodium hydride and 6.5 ml. of tetrahydrofuran, there is added a solution of 3.76 g. of diethylphosphonoacetaldehyde cyclohexylamine enamine in 20 ml. of anhydrous tetrahydrofuran under ice-cooling and stirring, and then stirring is continued for minutes. Then, a solution of 1.27 g. of benzaldehyde in 13 ml. of anhydrous tetrahydrofuran is added and the resulting solution is kept at room temperature for 2 hours under stirring. Thereafter, the product Worked up as usual manner is purified by vacuum distillation to afiord 1.22 g. of cinnamic aldehyde (77.2% yield) having b.p. 78 C./1.0 mm. Hg.

C01 max.

UV: x933? 287 my (6 22,400). IR: 1692, 1630 emf.

Semicarbazone: mp. 206-209 C.

EFMMPLE 14 3,3-ethylenedioxy-1 1 B-hydroxy-S, 17 pregnadien-Z l-al To a mixture of 39 mg. of 52.9% sodium hydride and 0.5 m1. of tetrahydrofuran, there is added a solution of 226 mg. of diethylphosphonoacetaldehyde cyclohexylamine enamine in 1.5 ml. of anhydrous tetrahydrofuran under ice-cooling and stirring, and then stirring is continued for 15 minutes. Then, a solution of 100 mg. of 3,3-ethylenedioxy-11B-hydroxy-5-androsten-17-one in 1.0 ml. of anhydrous tetrahydrofuran is added and the resulting solution is kept at room temperature for 19 hours under stirring. The reaction mixture is poured into icewater, extracted with dichloromethane, Washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield 234 mg. of residue. The residue is dissolved in a mixture of dichloromethane and tetrahydrofuran (5:1) and treated with a butter solution (pH 4.1), prepared from 10 ml. of 0.385 M tartaric acid and 10 ml. of 0.385 M sodium hydroxide, at room temperature for 38 hours under stirring. The reaction mixture is poured into Water, extracted with dichloromethane, washed with Water, dried over anhydrous sodium sulfate and evaporated to dryness to yield 149 mg. of residue, which is passed through a column of 3 g. of alumina. Eluate with benzene or benzene-dichloromethane (1:1) is recrystallized from dichloromethane-ether to afford 69 mg. of 3,3 ethylenedioxy-l 1,8-hydroxy-5, 17 (20 -pregnadien-21- al having mp. 224-226 C. Anal.Calcd. for C H O C, 74.16; H, 8.66. Found: C, 73.94; H, 8.63.

12 EXAMPLE 15 Cyclohexylidene acetaldehyde According to the same procedure as the above Examples, cyclohexanone is subjected to reaction with diethylphosphonoacetaldehyde cyclohexylamine enamine to yield cyclohexylidene acetaldehyde having b.p. 88-89 C./ 16 mm. Hg.

UV: X 240 my (6 15,200). IR:

max.

NMR: 5 (CDCI 6.86, 9.93 p.p.rn.

UV: A538? 273.5 m 1 (6 34,000).

EXAMPLE 16 2-cyclohexylidenepropionaldehyde To a mixture of 82 mg. of 52.9% sodium hydride and 0.5 ml. of tetrahydrofuran, there is added a solution of 497 mg. of 2-diethylphosphonopropionaldehyde cyclohexylamine enamine in 1.0 ml. of anhydrous tetrahydrofuran under ice-cooling and stirring. The stirring is continued for 15 minutes and a solution of 147 mg. of cyclohexanone in 1.0 ml. of anhydrous tetrahydrofuran is then added. The reaction mixture is kept at room temperature for 5.5 hours under stirring and then poured into icewater. The product is extracted with ether and washed with saturated sodium chloride aqueous solution, then the basic portion extracted with 20% tartaric acid. To the tartaric acid layer is added potassium carbonate under icecooling to be slightly basic. The precipitated product is extracted with ether, washed With saturated sodium chloride aqueous solution and evaporated to dryness to yield crude crystals, which on recrystallization from etherpentane afford the intermediary Schifi-base having m.p. 7778 C.

UV: 85, 95 246.5 mg. 6 24,200 IR: 9

Anal.-Calcd. for C H N: C, 82.13; H, 11.49; N, 6.38. Found: C, 82.00; H, 11.69; N, 6.15.

To a solution of this intermediary Schiff-base in 23 ml. of benzene, there is added 718 mg. of oxalic acid and 70 ml. of water and the solution is then refluxed for 1 hour under nitrogen atmosphere. After cooling, the benzene layer is separated and the aqueous layer is extracted with ether. The extract combined with the benzene layer is washed with 2 N sodium carbonate and saturated sodium chloride aqueous solution and evaporated to dryness to yield 152 mg. of residue. The residue is purified by vacuum distillation to afford 129 mg. of 2-cyclohexylidenepropionaldehyde (62.6% yield from cyclohexanone) having b.p. 60 C./0.10-0.15 mm. Hg (bath temperature). On the other hand, the residue obtained by the reaction with oxalic acid, without distilling, may be immediately converted to the 2,4-dinitrophenylhydrazone as crystals having m.p. 187-190 C. in 66.2% yield from cyclohexanone.

2,4-Dinitrophenylhydrazone2 chloromethane-ethanol.

recrystallized from di- UV: 35 228 m (6 13,400 259 (14,750 295 (8,900 389 (25,000 IR: 73 5 3292, 1619, 1590, 1884, 1137, 834 6m.

Ana1.-Calcd. for 0 .11.50.18 0, 56.59; H, 5.70; N, 17.60. Found: C, 56.50; H, 5.70; N, 17.40.

13 EXAMPLE 17 2-cyclohexylidene-3 -phenylpropionaldehyde To a mixture of 187 mg. of 52.9% sodium hydride and 1.5 ml. of tetrahydrofuran, there is added a solution of 2.905 g. of 3-phenyl-2-diethylphosphonopropionaldehyde cyclohexylamine enamine in 4.0 ml. of anhydrous tetrahydrofuran under ice-cooling and stirring. The stirring is continued for 15 minutes and a solution of 405 mg. of cyclohexanone in 4.0 ml. of anhydrous tetrahydrofuran is then added. The reaction mixture is refluxed for 3 hours. After cooling, the reaction mixture is poured into icewater, extracted with ether, washed with saturated sodium chloride aqueous solution and evaporated to dryness to yield 2.496 g. of residue. A portion (1.704 g.) of this residue is dissolved in 50 ml. of benzene and treated, according to the same procedure as Example 9, with 3.63 g. of oxalic acid and 146 m1. of water to yield 1.271 g. of residue. The residue is passed through a column of silica gel (Woelm; containing 10% of Water) and eluted with benzene or benzene-dichloromethane (1:1) to afford 408 mg. of cyclohexylidene-3-phenylpropionaldehyde (67.3% yield 2.496 g. of residue. A portion (1.704 g.) of this having m.p. 162-174" C. (recrystallized from dichloromethane-ethanol).

Anal.Calcd. for C H O N C, 63.94; H, 5.62; N, 14.21. Found: C, 63.64; H, 5.66; N, 14.50.

EXAMPLE 18 3,3-ethylenedioxy-1 1-oxo-5, 17 (20 -pregnadien-2l-al To a mixture of 26.9 mg. of 52.9% sodium hydride and 0.4 ml. of anhydrous tetrahydrofuran, there is added a solution of 155 mg. of diethylphosphonoacetaldehyde cyclohexylamine enamine in 1.0 ml. of anhydrous tetrahydrofuran under ice-cooling and stirring. The stirring is continued for 15 minutes and a solution of 68 mg. of 3,3- ethylenedioxy-S-androstene-11,17-dione in 0.7 ml. of anhydrous tetrahydrofuran is then added. The reaction mixture is kept at room temperature for 21 hours under stirring and then poured into ice-water. The product is extracted with ether, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield 171 mg. of residue. The residue is dissolved in 3.0 ml. of benzene and then 1.088 g. of sodium acetate, 480 mg. of acetic acid and 3.0 ml. of water are added. The resulting mixture is kept at room temperature for 21 hours under stirring and the product is extracted with ether, washed with water and evaporated to dryness to yield 126 mg. of residue, which is passed through a column of 4 g. of alumina. Eluate with benzene or benzene-dichloromethane is recrystallized from dichloromethane-ether to afiord 53.2 mg. of 3,3-ethylenedioxy-11-oxo-5,17(20)-pregnadien-21-al (72. 8% yield) having m.p. 208-212" C. -47.6- -2.2 (c. =0.397: chloroform). Anal.Calcd. for C H O C, 74.56; H, 8.16. Found: C, 74.29; H, 8.14.

EXAMPLE 19 1-forn1ylmethylene-6-methoxytetraline To a mixture of 155 mg. of 52.9% sodium hydride and 1.0 ml. of tetrahydrofuran, there is added a solution of 892 mg. of diethylphosphonoacetaldehyde cyclohexylamine enamine in 2.0 ml. of anhydrous tetrahydrofuran under ice-cooling and stirring, and then stirring is continued for 15 minutes. A solution of 200 mg. of 6-methoxy-a-tetralone in 2.0 ml. of anhydrous tetrahydrofuran is then added and the resulting solution is kept at room temperature for 6.5 hours under stirring. The reaction mixture is then poured into ice-Water, extracted With ether, washed with water, dried over anhydrous sodium sulfate and then evaporated to dryness to yield 790 mg. of syrupy residue. The residue is dissolved in 29 ml. of benzene and then 868 mg. of oxalic acid and 86 ml. of water are added.

The mixture is kept at room temperature for 13 hours under stirring and then extracted with ether. Ether extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield 114 mg. of crystalline residue, which on recrystallization from dichloromethane-ether affords 34 mg. of 1-formylmethylene-6- methoxytetraline (31% yield) having m.p. 89-90" C.

IR: 55,59 2774, 1656, 1610, 1591, 1151 emf.

Anal.--Calcd. for C H O C, 77.20; H, 6.98. Found: C, 76.85; H, 7.01.

EXAMPLE 20 According to the similar procedure as described above, a-(2,6,6-trimethyl 1 cyclohexenyl)-acetaldehyde is converted to u-(2,6,6-trimethyl-l-cyclohexenyl)-a-methylcrotonic aldehyde (b.p. 99-103" C./0.5 mm. Hg; identified as semicarbazone: m.p. 155-157 C.), cinnamalacetaldehyde to 7-phenylheptatrienal (m.p. 114-116 C.), and 2,7-dimethylocta-2,6-dien-4-yne-1,8-dial to 4,9-dimethy1- dodeca 2,4,8,10 tetraen-6-yne-l,12-dial (m.p. 162-163 C.), respectively.

EXAMPLE 21 Cinnamic aldehyde To a mixture of 590 mg. of 52.9% sodium hydride and 6.0 ml. of tetrahydrofuran, there is added a solution of of 3.80 g. of ethyl-2-cyclohexylaminovinyl phenylphosphinate in 20 ml. of anhydrous tetrahydrofuran and then the mixture is stirred for 20 minutes. A solution of 1.06 g. of benzaldehyde in 11 ml. of anhydrous tetrahydrofuran is then added and the resulting solution is kept at room temperature for 4 hours under stirring. The reaction mixture is then added into ice-water, extracted with ether, washed with water, dried over anhydrous sodium sulfate and evaporated to yield 3.16 g. of residue. To a solution of this residue in ml. of benzene, there is added 1.0 g. of oxalic acid and 300 ml. of water and the solution is then stirred for 14 hours at room temperature. Benzene layer is separated and the aqueous layer extracted with ether. The extract combined with the benzene layer is washed with Water, dried over anhydrous sodium sulfate and evaporated to dryness to yield 1.37 g. of residue, which on purification by vacuum distillation affords 0.96 g. of cinnamic aldehyde (72.5% yield) having b.p. 7 8 C./ 1.0 M mm. Hg.

EXAMPLE 22 a-Methylcinnarnic aldehyde To a mixture of 318 mg. of 52.9% sodium hydride and 3.0 ml. of tetrahydrofuran, there is added a solution of 2.15 g. of ethyl-(2-cyclohexylamino-l-methyl)vinyl phenylphosphinate in 12 ml. of anhydrous tetrahydrofuran, and then the mixture is stirred for 20 minutes. A solution of 530 mg. of benzaldehyde in 5.0 ml. of anhydrous tetrahydrofuran is then added and the resulting solution is kept at room temperature for 20 hours under stirring. According to the same procedure as Example 21, the reaction mixture is treated and then hydrolyzed with oxalic acid. The resulting product is purified by vacuum distillation to afford 469 mg. of u-methylcinnamic aldehyde (64.3% yield) having b.p. 131-132 C./1. 6 mm. Hg, identified as semicarbazone: m.p. 206-208 C. Anal.Calcd. for C H ON C, 65.00; H, 6.45; N, 20.68. Found: C, 65.13; H, 6.29; N, 20.51.

EXAMPLE 23 fl-Phenylcynnamic aldehyde To a mixture of 18 mg. of 52.9% sodium hydride and 3.0 ml. of tetrahydrofuran, there is added a solution of 2.05 g. of ethyl-2-cyclohexylaminovinyl phenylphosphinate in 11 ml. of anhydrous tetrahydrofuran, and then the mixture is stirred for 20 minutes. A solution of 911 mg. of benzophenone in 9.0 ml. of anhydrous tetrahy- Anal.-Calcd. for C H O: C, 86.51; H, 5.81. Found: C, 86.66; H, 5.90. Semicarbazone: m.p. 214-215 C.

EXAMPLE 24 Z-cyclohexylidenepropionaldehyde To a mixture of 218 mg. of 52.9% sodium hydride and 2.0 ml. of tetrahydrofuran, there is added a solution of 1.23 g. of ethyl-(2-cyclohexylamino-l-methyl)vinyl phenylphosphinate in ml. of anhydrous tetrahydrofuran, and the mixture is stirred for 20 minutes. A solution of 294 mg. of cyclohexanone in 3.0 ml. of anhydrous tetrahydrofuran is then added and the resulting solution is kept at room temperature for 7 hours under stirring. The reaction mixture is poured into ice-water, extracted with ether, washed with saturated sodium chloride aqueous solution and further extracted with 20% tartaric acid solution to remove the basic portion. The tartaric acid layer is treated with potassium carbonate under ice-cooling to make slightly basic. The product is then extracted with ether, washed with saturated sodium chloride aqueous solution and evaporated to dryness to yield crude crystals, which on recrystallization from ether-pentane afford the Schiff-base intermediate, having M.P. 7778 C., which is identical with an authentic specimen prepared in Example 16.

According to the same procedure as Example 16, this intermediate is hydrolyzed with oxalic acid in benzene and the product is purified by vacuum distillation to afford 324 mg. of 2-cyclohexylidenepropionaldehyde (58.8% yield) which is identified as 2,4-dinitrophenylhydrazone (m.p. 187-190 C.).

EXAMPLE 25 3-formylmethylene-Sa-androstan-17,8-01 benzoate To a mixture of 59 mg. of 52.9% sodium hydride and 1 ml. of tetrahydrofuran, there is added a solution of 380 mg. of ethyl-2-cyclohexylaminovinyl phenylphosphinate in 2.0 ml. of anhydrous tetrahydrofuran, and the mixture is then stirred for 20 minutes. A solution of 395 mg. of 17,6-benzoyloxy-5a-androstan-3-one in 3.0 ml. of anhydrous tetrahydrofuran is added and the resulting solution is kept at room temperature for 6.5 hours under stirring. According to the same procedure as Example 21, the reaction mixture is treated and then hydrolyzed with oxalic acid. The resulting product is recrystallized from ether to afford 298 mg. of 3-formylmethylene-5u-androstan-17,B-ol benzoate (71.0% yield), having m.p. 157- 158 C., which is identical with an authentic specimen prepared in Example 9.

EXAMPLE 26 17(20)-5a-pregnen-21-al Reaction of 5u-androstan-17-one with ethyl-2-cyclohexylaminovinyl phenylphosphinate, according to the same procedure as Example 25, affords l7(20)-5apregnen-21-al (recrystallized from ether) having ISO-152 C. in about 70% yield, which is identical with an authentic specimen prepared in Example 12.

16 EXAMPLE 27 5 a-formylethylenepregnane-3,20-dione According to the same procedure as Example 25, 3,3 20,20-bisethylenedioxy 5'01. forrnylpregnane is subjected to reaction with ethyl-2-cyclohexylaminovinyl phenylphosphinate. Hydrolysis with oxalic acid and subsequent deketallization with 70% acetic acid at 6070 C. atford 5a-formylethylenepregnane-3,20-dione having m.p. 140-144 C. in about yield, which is identical with an authentic specimen prepared in Example 11.

EXAMPLE 28 2-cyclohexylidene-3-phenylpropionaldehyde To a mixture of 364 mg. of 52.9% sodium hydride and 3.5 ml. of tetrahydrofuran, there is added a solution of 3.07 g. of ethy1-(1-benzyl-2-cyclohexylamino)vinyl phenylphosphinate in 4.0 m1. of anhydrous tetrahydrofuran under ice-cooling and stirring, and the mixture is then stirred for 20 minutes. A solution of 393 mg. of cyclohexanone in 4.0 ml. of anhydrous tetrahydrofuran is added and the resulting solution is refluxed for 4 hours. After cooling, the reaction mixture is poured into icewater, extracted with ether, then treated in the same manner as Example 21, and then further hydrolyzed with oxalic acid. The product is purified by passing through a column of silica gel to afford 411 mg. of 2-cyclohexylidene-3-phenylpropionaldehyde (48.1% yield), which is converted to 2,4-dinitrophenylhydrazone identical with an authentic specimen prepared in Example 17.

EXAMPLE 29 3,3-ethylenedioxy-1 l-oxo-5,l7 (21 -pregnadien-21-al To a mixture of 136 mg. of 52.9% sodium hydride and 1.0 ml. of tetrahydrofuran, there is added a solution of 880 mg. of ethyl-2-cyclohexylaminovinyl phenylphosphinate in 7 ml. of anhydrous tetrahydrofuran, and the mixture is then stirred for 20 minutes under ice-cooling. A solution of 340 mg. of 3,3-ethylenedioxy-5-androstene- 11,17-dione in 3 ml. of anhydrous tetrahydrofuran is added and the resulting solution is kept at room temperature for 24 hours under stirring. The reaction mixture is poured into ice-water, extracted with ether, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield 930 mg. of residue. To a solution of this residue in 16 ml. of benzene, there is added 5.3 g. of sodium acetate, 2.31 g. of acetic acid and 16 ml. of water, and the resulting mixture is kept at room temperature for 21 hours under stirring. The product is extracted with ether, washed with water and evaporated to dryness to yield a residue, which on crystallization from dichloromethane-ether affords 263 mg. of 3,3-ethylenedioxy 11 oxo-5,17(20)-pregnadien-21-al (71.0% yield) having m.p. 208212 C., which is identical with an authentic specimen prepared in Example 18.

We claim:

1. A process for preparing a compound of the formula:

wherein R is a lower alkyl group, R is a member selected from the group consisting of R 0, a lower alkyl group, an aralkyl group of 7-8 carbon atoms and an aryl group of 6-7 carbon atoms, and R is a member selected from the group consisting of an acyclic or cyclic alkyl group of 1-6 carbon atoms and an aryl group of 6-7 carbon atoms, which comprises reacting a compound of the formula:

P-omoH wherein R and \R each has the same meanings as described above, with a compound of the formula:

wherein R has the same meanings as described above, in an organic solvent at a temperature ranging from 0 C. to 120 C.

2. A process as claimed in claim 1, wherein an organic solvent is a member selected from the group consisting of methanol, ethanol, n-propanol, t-butanol, benzene, toluene and tetrahydrofuran.

18 References Cited UNITED STATES PATENTS 3,337,563 8/1967 Skaletzky 260-583 H X OTHER REFERENCES West, Jor. of Chemical Education, vol. 40, No. 4, 1963, pp. 194400.

10 ANTON H. SU'ITO, Primary Examiner US. Cl. X.R. 260944 

